Biosynthesis of the two variant forms of plasma apolipoprotein B and the multiple isoforms of plasma apolipoprotein A-I was studied in perfused rat livers. The relative amounts of the two apolipoprotein B variants produced was influenced by the diet, with implications for the metabolic fate of the associated lipoproteins. Both newly-synthesized variants were incorporated into all sizes of very low density lipoproteins produced, with little segregation into different sized particles. Significant amounts of the smaller variants sometimes appeared in high-density lipoproteins. Hepatic release of the smaller variant was relatively delayed, suggesting a difference in the assembly or release of lipoprotein particles containing the two proteins. Apolipoprotein A-I, the major protein of serum high-density lipoproteins, was found to exhibit polymorphism, circulating in serum as two major isoproteins and several minor species. Rat liver synthesized all of the isoproteins, but not in the proportions observed in serum. Very little of the most abundant serum isoform was produced. These findings suggest that the two major apolipoprotein A-I isoforms may be interconverted by extra-hepatic tissues or may differ in their site of biosynthesis or in their catabolic rate.